Advancing oncology drug therapies for sub-Saharan Africa

Cancer incidence is rising across sub-Saharan Africa (SSA), and is often characterized by late-stage presentation, early age of onset and poor survival. While a number of oncology drugs are now improving the length and quality of life for cancer patients in high-income countries, significant disparities in access to a range of oncology therapeutics exist for SSA. A number of challenges to drug access such as drug costs, lack of infrastructure and trained personnel must be urgently addressed to advance oncology therapies for SSA. We present a review of selected oncology drug therapies that are likely to benefit cancer patients with a focus on common malignancies in SSA. We collate available data from seminal clinical trials in high-income countries to highlight the potential for these therapeutics to improve cancer outcomes. In addition, we discuss the need to ensure access to drugs within the WHO Model List of Essential Medicines and highlight therapeutics that require consideration. Available and active oncology clinical trials in the region is tabulated, demonstrating the significant gaps in access to oncology drug trials across much of the region. We issue an urgent call to action to address drug access due to the predicted rise in cancer burden in the region in coming years.


Introduction
Cancer incidence is rising across sub-Saharan Africa (SSA), and is often characterized by latestage presentation, early age onset, aggressive disease and poor survival [1]. The distinct cancer epidemiology in SSA is driven by a high burden of infectious disease-related cancers, combined with rising lifestyle-related cancers due to factors such as increased tobacco use and excess body weight [2]. In addition, changes to female reproductive patterns and an ageing population are contributing to cancer risks [1]. Highly prevalent infectious diseases in SSA are causally associated with malignancies including cervical cancer and Kaposi sarcoma [3]. Cancers for which preventative measures are routinely offered in high income countries (HIC), such as breast, prostate and cervical cancer are advanced at presentation in SSA, because of a lack of organized screening and early detection programs [4]. In addition, evidence suggests that differences a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 immunodeficiency syndrome (AIDS) epidemic. The incidence of KS in SSA has increased 20-fold since the onset of the HIV epidemic in the early 1980s [19]. KS is relatively rare globally, however, there were approximately 34,000 new cases and 15,000 deaths in 2020, largely in Southern and Eastern Africa. There are regional variations in SSA with highest age-standardised incidence rates (ASIR) found in Southern Africa approximating 9/100,000, compared with 6/100,000 in Eastern Africa, and 0.9/100,000 in Western Africa. 1 Available data from the Africa Cancer Registry Network found a rapid increase in KS prior to antiretroviral therapy (ART), however, an overall average decline after ART between 2000 and 2010 and 2011-2016 [20]. While ART has reduced the incidence of AIDS associated KS, there remains ongoing significant morbidity and mortality from KS in the region [21].
Management for AIDS associated KS is driven by tumor location, extent of disease, CD4 + T cell count and overall clinical condition. Since most cases of KS that require intensive treatment are associated with HIV, it is imperative for all patients living with HIV to receive ART. Cutaneous lesions can be treated with ART, topical alitretinoin or imiquimod cream, radiation therapy, intralesional vinblastine chemotherapy, or local excision. However, in SSA, patients often present later in the disease course with advanced cutaneous, oral, visceral, or nodal disease. In HICs, chemotherapy with liposomal daunorubicin is recommended for advanced disease given its favorable toxicity profile.
Paclitaxel, however, has similar efficacy with 78% 2-year survival compared to 79% for liposomal daunorubicin (Table 1) [22]. A study of AIDS-associated Kaposi sarcoma in SSA and South America demonstrated the superiority of paclitaxel compared to etoposide, and bleomycin with vincristine. These findings were significant in that paclitaxel survival benefits may be comparable to liposomal daunorubicin, yet it is much more affordable and readily available in SSA [23]. As the first large clinical trial comparing chemotherapy for KS in SSA in over a decade, this study underscores the paucity of clinical trials for KS in SSA compared to the significant burden of disease in the region (Table 2). There is comparatively less interest in studying novel therapies for KS, however, one recently published trial of 17 patients in France demonstrated preliminary efficacy of pembrolizumab [24].

Prostate cancer
Prostate cancer is the leading cause of cancer death among men in 48 countries, including many in SSA [19]. There is, however, substantial regional variation in the incidence of prostate cancer across SSA, with the highest ASIR in the region found in Southern Africa approximating 66/100,000 in 2020, compared with Western and Eastern Africa where ASIR approximates 30/100,000 [1]. Mortality rates are high in SSA, with age-standardized mortality rates (ASMR) in 2020 approximating 22/100,000, 20/100.000 and 16/100,000 in Southern, Western and Eastern Africa respectively. While data are very limited, a median overall survival of only 11 months was reported for metastatic castrate resistant prostate cancer (mCRPC) in a series from Nigeria [25]. Treatment with surgical castration is widespread in SSA, with limited use of luteinizing hormone releasing hormone (LHRH) analogues, oral anti-androgens (bicalutamide and flutamide), or docetaxel [26,27]. For metastatic prostate cancer, androgen deprivation therapy can provide symptom relief and improve survival. The disease invariably becomes resistant to hormone therapy however, leading to development of mCRPC.
Newer generation oral hormone therapy may have an expanded role in SSA, in both the castrate-sensitive and castrate-resistant settings. Abiraterone is a well-tolerated drug which blocks synthesis of androgens and is given in combination with low dose prednisone. Based on data showing significant survival benefit, abiraterone with prednisone was initially approved by the US FDA in 2011 for patients with mCRPC who had received prior chemotherapy and then expanded to chemotherapy-naive patients. Due to significant benefits in the castrate-sensitive group, indications were expanded in 2018 for patients with newly diagnosed castratesensitive metastatic prostate cancer. Overall, the therapy was well tolerated with notable side effects being hypertension and hypokalemia [28]. Updated data from the STAMPEDE study demonstrated a median survival of 6.6 years with addition of abiraterone with prednisone to standard androgen deprivation therapy (ADT), compared with 3.8 years with ADT alone [29].
Survival benefits have also been demonstrated with addition of either enzalutamide or apalutamide to ADT in patients with newly diagnosed mCRPC ( Table 1). The addition of chemotherapy with docetaxel also has a demonstrated survival benefit [30]. The emerging evidence clearly demonstrates that intensifying therapy for men with metastatic prostate cancer earlier in disease course, even in the castrate-sensitive setting, has clear survival advantage. PARP inhibitors, such as olaparib, have a role in patients with mCRPC with certain molecular profiles, particularly BRCA 2 [31]. Molecular profiling capabilities are, however, required, and the extent of BRCA 2 mutations in SSA populations remains poorly characterized at present. Therapeutic options including chemotherapy, immunotherapy and radiopharmaceuticals also clearly have an established role for management of mCRPC, however rapidly expanding availability of newer generation oral hormone therapy is likely to have important impacts. This is reflected by the inclusion of abiraterone with prednisone in the World Health Organization (WHO) Model List of Essential Medicines (MLEM) ( Table 2). Though enzalutamide and apalutamide also have proven benefit in the castrate-sensitive metastatic prostate cancer setting, abiraterone may be preferred for several reasons. As the first of the newer generation hormone therapies to become available, abiraterone will likely have multiple generic options available first, with hopes of reduced pricing in the future. Cost savings could also be achieved by alternative dosing with food [32].

Breast cancer
The incidence rates of breast cancer in SSA are low compared to HICs, however, these rates are rapidly rising [6]. In Southern Africa ASIR approximated 50/100,000 in 2020 with mortality rates among the world's highest due to late-stage presentation and lack of screening programs [1]. In addition, evidence suggests a higher percentage of hormone receptor negative or triple negative disease in the region, both of which are associated with a poorer prognosis [33]. Treatment for breast cancer greatly differs based on hormonal status and human epidermal growth factor (HER2) expression status. Accurate profiling, however, is dependent on methods used for tissue collection, fixation, and immunohistochemical staining, which are not standardized in SSA. Hormonal therapy, including drugs such as tamoxifen and aromatase inhibitors (anastrozole, letrozole, or exemestane), is indicated for hormone-receptor positive tumors. While access to aromatase inhibitors remains limited, tamoxifen is inexpensive and even free of charge in some countries, making it the most readily available drug for breast cancer in SSA [33][34][35]. Consequentially, patients whose hormone receptor status is unknown may empirically receive tamoxifen. While routine testing for hormone receptor status prior to treatment initiation is uncommon, in a recent meta-analysis of five East African countries, 55% of women with breast cancer were estrogen receptor (ER) positive compared to 72% in the United States [36]. However, only those who are hormone receptor positive are expected to benefit from treatment with tamoxifen, hence patients are often exposed to the potential harms of tamoxifen with no therapeutic advantage [37,38]. The predominant chemotherapy regimens for patients with HER2 negative disease are anthracycline based regimens such as doxorubicin and cyclophosphamide followed or preceded by a taxane (paclitaxel or docetaxel), or anthracycline free regimens such as docetaxel and cyclophosphamide. The WHO MLEM includes agents such as carboplatin, cyclophosphamide, doxorubicin, and paclitaxel, but availability and access to these drugs appears limited. For example, in a population-based registry study of 834 patients in 11 countries in SSA, only 33.6% received chemotherapy, of which 52% received an anthracycline based regimen and 32% received an anthracycline with a taxane [39].
The advent of HER2 targeted drugs have transformed the management and prognosis of HER2 positive breast cancer in HICs. The HERA trial established the role of trastuzumab after adjuvant chemotherapy in HER2 positive breast cancer patients by demonstrating significantly improved disease-free survival (DFS) and overall survival (OS) [40,41]. Unfortunately, trastuzumab has historically been cost-prohibitive [42]. While some studies estimate that 50% of facilities in SSA have trastuzumab available, less than 5% of patients were able to afford it [33]. The advent of biosimilars since 2019, however, are now facilitating price reductions to $600-800 dollars per vial in SSA countries (Table 2) [43].
There is a high incidence of triple negative breast cancer (TNBC) in SSA, and this breast cancer pathologic subtype is negatively associated with survival [44,45]. Two immunotherapy drugs, atezolizumab and pembrolizumab, are approved for use in the US in combination with chemotherapy for patients with metastatic TNBC whose tumors have high expression of PD-L1, based on the results of the IMpassion130 and KEYNOTE-355 trials [46,47]. Unfortunately, predictive biomarker testing that is required to identify patients with PD-L1 positive tumors is not widely available in SSA. In addition, immunotherapy is associated with rare but serious adverse events that require routine monitoring and specialized management. Therefore, there is a need to develop further training and infrastructure to support the use of these effective drugs.
Other targeted drugs are integral parts of the treatment landscape for metastatic breast cancer, such as targeting PI3Kinase, mammalian target of rapamycin, and cyclin dependent kinases (CDKs). Of these drugs, the CDK 4/6 inhibitors have shown the greatest benefit and the fewest side effects. The addition of CDK4/6 inhibitors to hormonal therapy with aromatase inhibitors or fulvestrant showed a significant and clinically meaningful survival benefit in firstand second-line metastatic settings (see Table 1) [48][49][50]. Given the limited toxicity profile of CDK4/6 inhibitors compared to chemotherapy and their oral administration, they have the potential to improve care more widely in SSA (see Table 2). The challenge for implementation is the elevated cost of CDK4/6 inhibitors, as well as the limited availability of tumor profiling.

Cervical cancer
In SSA, cervical cancer (CC) is the leading cause of female cancer related death and the second most common cancer among women [4,8]. Globally, the highest incidence and mortality rates are in SSA with ASIR of 40/100,000 in Eastern Africa and 37/100,000 in Southern Africa in 2020 [1]. This higher incidence in SSA parallels HIV-infection rates-as an AIDS-defining illness HIV-positive women have a 6-fold higher risk of CC due to higher infection and persistence rates of cervical oncogenic Human Papilloma Virus (HPV) genotypes. Primary prevention through adolescent HPV vaccination programs have been launched in SSA, however, will take several decades to impact CC incidence [51]. In addition, expanding coverage of accessible, affordable, and high-performance cervical screening programs has been challenging due to financial, logistic, and sociocultural barriers [52]. Due to the preventable nature of CC, the WHO has launched a strategy for the global elimination of cervical cancer focusing on rapid scale-up of vaccination, screening and treatment of pre-cancers and CC.
The standard of care for management of patients with locally advanced CC disease is chemoradiation. The preferred chemotherapy in conjunction with radiation is cisplatin [53]. A study which included twenty-nine centers from twelve SSA countries found that appropriate chemotherapeutic agents were available in 86% of centers. However, one-third of centers reported having to delay treatments or substitute with alternate chemotherapeutic agents due to inconsistent supply. In addition, almost half of the centers utilized neoadjuvant chemotherapy due to delays in availability of surgery and radiotherapy [54].
Radiotherapy is integral to the management of advanced CC but there is limited access in SSA due to the need for trained personnel for equipment maintenance and optimal implementation [55]. In addition, maintenance and repair of linear accelerators and lack of access to a stable and reliable power supply may result in downtime of equipment, ultimately leading to treatment delays for patients [56]. In an observational study of 632 patients from eight SSA countries, only 13% of patients with known stage I-III CC received primary external beam radiation therapy and brachytherapy [57].
In addition to concurrent chemoradiotherapy for localized disease, chemoimmunotherapy (with pembrolizumab in combination with a platinum doublet) was FDA approved in October 2021 for persistent, recurrent, or metastatic cervical cancer patients whose tumors are PD-L1 positive [58]. Given many women progress while waiting for radiotherapy, improving access to testing for PD-L1 status and the capacity of providers with expertise in managing immunotherapy, should be considered to expand the feasibility of this option in SSA.

Lung cancer
The burden of lung cancer in SSA is expected to increase in parallel to the tobacco epidemic, with greater affordability and marketing of tobacco products in the region [4]. In SSA, lung cancer rates are highest in Southern Africa with ASIR of 27/100,000 in 2020 compared with Eastern Africa with ASIR of 4/100,000 [1]. In HICs, molecular targeted therapies for lung cancer have achieved substantial survival benefits. Current standards for management of lung cancer involve first identifying histologic subtype via immunohistochemistry (IHC) to differentiate between small cell (SCLC), non-small cell (NSCLC), or squamous cell lung cancer (SLC). In most HICs, testing NSCLC for mutations in EGFR, BRAF, KRAS, and ALK and ROS1 gene rearrangements via liquid biopsy, next-generation sequencing (NGS), and/or fluorescent in-situ hybridization is common [59,60]. At a minimum, mutations in EGFR, ALK status, and PDL1 status via IHC should be known before starting first-line systemic therapy because regimens for patients with these mutations can differ drastically [59].
Traditionally, recommended treatment for patients with metastatic NSCLC has been chemotherapy with a platinum-based combination regimen. However, median survival for patients receiving chemotherapy alone approximates to 10 months, with 1-year survival of only 30-40%, and 5-year overall survival of approximately 6% [61][62][63][64][65][66]. Survival rates are higher for stage IV NSCLC patients who are eligible for either targeted therapy or immunotherapy regimens, which increased overall survival from 10 to 24 months in those receiving EGFR-tyrosine kinase inhibitor (TKI) therapy versus those who did not [67][68][69][70][71][72]. Afatinib, erlotinib and gefitinib are therefore included in the WHO MLEM. However, patients often develop mutations which result in resistance to these agents. Osimertinib, which inhibits both EGFR sensitizing mutations and T790M, a common resistance mutation in EGFR mutated NSCLC, was approved in 2020 in the United States, however, is not listed in the WHO MLEM at present. Osimertinib, has achieved median overall survival exceeding 45 months, far greater than other TKIs. [73]. The notable impact of osimertinib for NSCLC suggests that it should be the TKI of choice and considered in the WHO MLEM.
In the population of stage IV NSCLC patients without a driver mutation, immunotherapy with pembrolizumab is recommended either as a single agent in patients with high PDL1 expression, or in combination with chemotherapy in those with low PDL1 expression. In patients with PDL1 expression in at least 50% of tumor cells, overall survival is doubled in patients who receive pembrolizumab monotherapy compared with those who receive chemotherapy (30 vs 14.2 months) [74]. Long-term data from trials have shown 5-year survival for patients upwards of 23% for those who received first-line pembrolizumab monotherapy [66,68]. Overall survival was also improved by chemotherapy regimens combined with pembrolizumab regardless of PD-L1 expression levels [75].
The number of agents that are approved and under investigation for NSCLC are increasing worldwide, however, access remains extremely limited in most settings in SSA (Table 2) [76]. One review of lung cancer management in South Africa noted that for private sector patients with EGFR mutations, only erlotinib is available for first line use, osimertinib is available in the second line setting and crizotinib is the only drug available for ALK positive patients [76].
For management of NSCLC to be optimal in SSA, identifying mutations in EGFR and PDL1 expression are essential to direct care. In addition, EGFR inhibitors, particularly osimertinib, and immunotherapy, particularly pembrolizumab, are two targeted therapies that have the potential to improve outcomes of NSCLC patients in SSA if given as first-line.

Tissue agnostic therapeutics for multiple solid tumors
Both hereditary and sporadic cancers arising at several anatomical sites including colon, rectum, endometrium, ovary and gastric adenocarcinoma may have mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), which have treatment implications [77]. In an analysis of MSI-H in 39 tumor types across 11,139 samples, MSI-H was found in 31% of endometrial cancers, 19% of stomach and 19.7% of colon adenocarcinomas [78]. While far more research is needed, available data suggests even higher rates of MSI-H were found in solid tumors from SSA. For example, in a sample of 90 colorectal cancer biospecimens in Ghana and 83 specimens in Nigeria, MSI-H was found in 41% and 43% of samples respectively [79,80]. Another study of 83 cases from KwaZulu Natal in South Africa, found MSI-H in 31.3% of colorectal cancer patients below age 35 years, and 12% in cases over 50 years [81].
The US FDA granted accelerated approval of pembrolizumab in May 2017 for patients with advanced previously treated solid tumors found to be MSI-H which has heralded the potential for histology-agnostic management regardless of site of origin for solid tumors [82]. Pembrolizumab approval was based on safety and efficacy results in 149 patients with MSI-H solid tumors that had progressed after standard treatment, who were enrolled in one of five multicenter, single-arm clinical trials (KEYNOTE-016, -164, -012, -028, and -158) [83]. The overall response rate was 39.6%, and importantly, responses lasted six months or more for 78% percent of responders, with 7.4% achieving complete responses [84].
Therapeutics that are tissue -agnostic raise the prospect of enabling the use of a select range of drugs across a wide range of solid tumors, with potential advantages in terms of costs, training and infrastructure needs in resource limited settings in SSA, especially if research suggests higher rates of MSI-H among SSA populations. A small number of trials of pembrolizumab which are histology-agnostic are, therefore, being conducted in South Africa evaluating gastro-intestinal and gynecological cancers.

Discussion
In SSA, the choice of public sector pharmaceuticals is often guided by the WHO MLEM, which are selected based on three broad criteria including disease prevalence and public health relevance, evidence of clinical efficacy and safety, and comparative cost-effectiveness. In addition, resource stratified guidelines are published by the National Comprehensive Cancer Network, however, evidence regarding the translation of guidelines into real-world practice is lacking. A survey of oncologists across low-, middle-, and high-income nations demonstrated concordance with the WHO MLEM but found significant barriers to the availability of therapies included in the WHO MLEM [85]. While even basic levels of palliative care or consistent supply of cytotoxic agents are still not widely available in many SSA settings, the inclusion of immunotherapies in the 2019 WHO MLEM signals an increasing recognition of the potential advantages of precision therapeutics in LMICs. While the 2019 MLEM only listed immunotherapy for metastatic melanoma due to high prices and concerns regarding effective administration in settings without appropriate infrastructure, one could argue that if capacity is built for treatment of melanoma, wider indications to NSCLC and other solid tumors will be feasible, widening the population for which quality of life and survival benefits may be realized.
The availability of molecular profiling of cancers if of paramount importance, particularly for certain cancers such as lung cancer for which targeted therapies have had a major impact on prognosis.
The presence of BRCA1/2 mutations in breast and prostate cancer, as well as BRAF mutations in melanoma, are other examples where molecular profiling can impact cancer therapeutics. Unfortunately, data on genomic profiles of cancer in patients in SSA is extremely limited [86]. Of worldwide cancer publications addressing genomics, only 0.016% evaluated people from SSA. Authorship by researchers based in SSA was limited even in manuscripts evaluating African populations, which was noted as a barrier to advancing the knowledge base in this field [87]. Rotimi et al performed a comprehensive literature review evaluating the published literature on cancer genomics in African populations between 1990-2019. Overall, there was a paucity of data, with the majority of SSA populations remaining largely unstudied. While breast cancer was studied most extensively, studies were predominantly limited to populations in North Africa which may not be representative of SSA. BRCA1 and BRCA2 mutations were noted in high frequency in Nigerian women, and some studies included South African and Senegalese populations. Data regarding genomic alterations in populations of prostate cancer patients in SSA was minimal, including data on frequency of BRCA1, BRCA2 or other homologous recombination repair genes [88]. For lung cancer, most notably EGFR, ALK and PD-L1 expression has had a significant impact on management, however, there is very limited data available of molecular profiles of lung cancer patients in SSA. Available data on EGFR expression in African populations is limited to North African populations [89].
We recognize that costs and cost-effectiveness concerns are important factors in realistically increasing availability of a broad range of oncology drug therapies in SSA. The moral need, however, to advance therapeutics and reduce the significantly high case-fatality rates from cancer in SSA remains an urgent global imperative. As such, the need for high levels of investment in cancer care has been acknowledged by all member states of the World Health Assembly in 2017, with the scale up national cancer prevention and control aligned to achieving the 2030 Agenda for Sustainable Development. To this end, several global organizations are challenging cost pressures such as the WHO medicines patent program, pooled procurement approaches, voluntary licensing and there are moves by the World Economic Forum to create enabling governance, regulatory and ethical environments to broaden the reach of precision therapies and diagnostics world-wide [90]. There is a need to harness the global drive to develop newer therapeutics that can transform cancer care, and global interest in including more diverse patient populations in clinical trials. Historically, a number of barriers including laboratory infrastructure, trained personnel and slow regulatory approval processes have delayed successful implementation of oncology clinical trials in SSA [91]. Future efforts, however, must expand clinical trial capacity to ensure inclusion of SSA populations in new and pre-clinical studies to improve access to the pipeline of new therapeutics, while forging avenues to expand access to existing approved therapeutics in SSA. Furthermore, in coming years, it is likely that generics and biosimilars will rapidly introduce new oncology drug pricing competition bringing the promise of advanced therapies to the emerging economies of SSA.